PROJECT SUMMARY Osteoarthritis (OA) is the most common form of arthritis in older adults and affects nearly 15% of the world population, including 68% of Americans over the age of 55, at costs of over $100 billion annually. In addition to aging, the trauma of a sports or military injury can also cause osteoarthritis in younger adults. A wide range of drugs have been employed to relieve pain and alter the natural course of the disease, but due to the rapid clearance of the drugs by the synovial fluid, all of the drugs have half-lives only on the order of minutes and must be repeatedly administered in high dosages. These findings suggest that traditional drug administration protocols are inefficient for the treatment of OA, and that drug delivery approaches that can target the dense extracellular matrix of the OA joint could represent a cost-effective method for increasing drug efficacy. We propose a novel approach to this problem that will exploit interactions between collagen-like peptides and natural collagens to develop a new thermoresponsive paradigm for the treatment of OA. We will evaluate collagen-peptide-coated, hollow nanoparticles that can be assembled and disassembled at therapeutically relevant temperatures. The nanoparticles will be assembled and loaded with cargo via the interactions of thermoresponsive domains that are conjugated to collagen-like peptides, and the nanoparticles will be localized to remodeled collagen via strand exchange interactions that have been previously shown to be competent for nanoparticle immobilization to collagen films. We will employ a range of spectrometry, light scattering, and microscopy methods to analyze nanoparticle formation, cargo loading, and localization to collagen films and explants of human OA cartilage. We will also conduct a series of assays to characterize the retention, release, and immunocompatibility of the nanoparticles in an in vivo murine model of OA. Although the focus of the proposed work is on increasing the effectiveness of therapies for OA, it will also lay the foundation for more effective early diagnostic approaches for OA and the ability to target other diseases.